The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions including organelle biogenesis, membrane trafficking or remodeling, and cell division and migration. Mutations in BAR containing proteins have been linked to diseases and their inactivation in cells leads to altered membrane dynamics. A BAR domain with an additional N-terminal amphipathic helix (an N-BAR) can drive membrane curvature. These N-BAR domains are found in amphiphysins and endophilins, among others. BAR domains are also frequently found alongside domains that determine lipid specificity, such as the Pleckstrin Homology (PH) and Phox Homology (PX) domains which are present in beta centaurins (ACAPs and ASAPs) and sorting nexins, respectively. A FES-CIP4 Homology (FCH) domain together with a coiled coil region is called the F-BAR domain and is present in Pombe/Cdc15 homology (PCH) family proteins, which include Fes/Fes tyrosine kinases, PACSIN or syndapin, CIP4-like proteins, and srGAPs, among others. The Inverse (I)-BAR or IRSp53/MIM homology Domain (IMD) is found in multi-domain proteins, such as IRSp53 and MIM, that act as scaffolding proteins and transducers of a variety of signaling pathways that link membrane dynamics and the underlying actin cytoskeleton. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The I-BAR domain induces membrane protrusions in the opposite direction compared to classical BAR and F-BAR domains, which produce membrane invaginations. BAR domains that also serve as protein interaction domains include those of arfaptin and OPHN1-like proteins, among others, which bind to Rac and Rho GAP domains, respectively.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  16 FTAHTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQTEINSLRASFDSLKQQMENVGSSHIQLA 95
Cdd:cd07671    1 FTLNTGYEILLQRLLDGRKMCKDVEELLKQRAQAEERYGKELVQIARKAGGQTEINTLKASFDQLKQQIENIGNSHIQLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  96 LTLREELRSLEEFRERQKEQRKKYEAVMDRVQKSKLSLYKKAMESKKTYEQKCRDADDAEQAFERISANGHQKQVEKSQN 175
Cdd:cd07671   81 GMLREELKSLEEFRERQKEQRKKYEAVMERVQKSKVSLYKKTMESKKTYEQRCREADEAEQTFERSSSTGNPKQSEKSQN 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916 176 KAKQCKDSAAEAERVYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNALWVHSNQLSMQCVKDDELYEEVRLT 255
Cdd:cd07671  161 KAKQCRDAATEAERVYKQNIEQLDKARTEWETEHILTCEVFQLQEDDRITILRNALWVHCNHFSMQCVKDDELYEEVRTT 240

                 ..
gi 966952916 256 LE 257
Cdd:cd07671  241 LE 242

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Proline-Serine-Threonine Phosphatase-Interacting Protein 1 (PSTPIP1), also known as CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  16 FTAHTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQTEINSLRASFDSLKQQMENVGSSHIQLA 95
Cdd:cd07671    1 FTLNTGYEILLQRLLDGRKMCKDVEELLKQRAQAEERYGKELVQIARKAGGQTEINTLKASFDQLKQQIENIGNSHIQLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  96 LTLREELRSLEEFRERQKEQRKKYEAVMDRVQKSKLSLYKKAMESKKTYEQKCRDADDAEQAFERISANGHQKQVEKSQN 175
Cdd:cd07671   81 GMLREELKSLEEFRERQKEQRKKYEAVMERVQKSKVSLYKKTMESKKTYEQRCREADEAEQTFERSSSTGNPKQSEKSQN 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916 176 KAKQCKDSAAEAERVYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNALWVHSNQLSMQCVKDDELYEEVRLT 255
Cdd:cd07671  161 KAKQCRDAATEAERVYKQNIEQLDKARTEWETEHILTCEVFQLQEDDRITILRNALWVHCNHFSMQCVKDDELYEEVRTT 240

                 ..
gi 966952916 256 LE 257
Cdd:cd07671  241 LE 242

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 966952916   360 PAQEYRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERN-GQRGFVPGSYLE 414
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGrGKEGLFPSNYVE 56

Fes/CIP4, and EFC/F-BAR homology domain; Alignment extended from. Highly alpha-helical. The cytosolic endocytic adaptor proteins in fungi carry this domain at the N-terminus; several of these have been referred to as muniscin proteins. These N-terminal BAR, N-BAR, and EFC/F-BAR domains are found in proteins that regulate membrane trafficking events by inducing membrane tubulation. The domain dimerizes into a curved structure that binds to liposomes and either senses or induces the curvature of the membrane bilayer to cause biophysical changes to the shape of the bilayer; it also thereby recruits other trafficking factors, such as the GTPase dynamin. Most EFC/F-BAR domain-family members localize to actin-rich structures.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 966952916   21 GYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQ-----TEINSLRASFDSLKQQMENVGSSHIQ 93
Cdd:pfam00611   1 GFKVLLKRLKQGIKLLEELASFLKERAEIEEEYAKKLQKLAKKFLKKkkkpeDDGGTLKKAWDELLTETEQLAKQHLK 78

MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916   45 QRAQAEERYGKELVQIARKAGGQTEINSLRASfDSLKQQMENVGSSHIQLALTLREELRSLEEFRERQKEQRKKYEAVMD 124
Cdd:PTZ00121 1618 AKIKAEELKKAEEEKKKVEQLKKKEAEEKKKA-EELKKAEEENKIKAAEEAKKAEEDKKKAEEAKKAEEDEKKAAEALKK 1696

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  125 RVQKSklslyKKAMESKKTYEQKCRDADDAEQAFE--RISANGHQKQVEKSQNKAKQCKDSAAEaervyRQSITQLEKVR 202
Cdd:PTZ00121 1697 EAEEA-----KKAEELKKKEAEEKKKAEELKKAEEenKIKAEEAKKEAEEDKKKAEEAKKDEEE-----KKKIAHLKKEE 1766

                         170       180
                  ....*....|....*....|.
gi 966952916  203 AEWEQEHRTTCEAFQLQEFDR 223
Cdd:PTZ00121 1767 EKKAEEIRKEKEAVIEEELDE 1787

Uncharacterized conserved protein YraI [Function unknown];

                         10        20        30
                 ....*....|....*....|....*....|....*
gi 966952916 380 LSAGDILEVI-LEGEDGWWTVERNGQRGFVPGSYL 413
Cdd:COG4991   47 LPAGATVTVLgCTSGGGWCKVSYGGQRGWVSARYL 81

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Proline-Serine-Threonine Phosphatase-Interacting Protein 1 (PSTPIP1), also known as CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  16 FTAHTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQTEINSLRASFDSLKQQMENVGSSHIQLA 95
Cdd:cd07671    1 FTLNTGYEILLQRLLDGRKMCKDVEELLKQRAQAEERYGKELVQIARKAGGQTEINTLKASFDQLKQQIENIGNSHIQLA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  96 LTLREELRSLEEFRERQKEQRKKYEAVMDRVQKSKLSLYKKAMESKKTYEQKCRDADDAEQAFERISANGHQKQVEKSQN 175
Cdd:cd07671   81 GMLREELKSLEEFRERQKEQRKKYEAVMERVQKSKVSLYKKTMESKKTYEQRCREADEAEQTFERSSSTGNPKQSEKSQN 160

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916 176 KAKQCKDSAAEAERVYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNALWVHSNQLSMQCVKDDELYEEVRLT 255
Cdd:cd07671  161 KAKQCRDAATEAERVYKQNIEQLDKARTEWETEHILTCEVFQLQEDDRITILRNALWVHCNHFSMQCVKDDELYEEVRTT 240

                 ..
gi 966952916 256 LE 257
Cdd:cd07671  241 LE 242

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 2; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Proline-Serine-Threonine Phosphatase-Interacting Protein 2 (PSTPIP2), also known as Macrophage Actin-associated tYrosine Phosphorylated protein (MAYP), is mostly expressed in hematopoietic cells but is also expressed in the brain. It is involved in regulating cell adhesion and motility. Mutations in the gene encoding murine PSTPIP2 can cause autoinflammatory disorders such as chronic multifocal osteomyelitis and macrophage autoinflammatory disease. PSTPIP2 contains an N-terminal F-BAR domain and lacks the PEST motifs and SH3 domain that are found in PSTPIP1. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  17 TAHTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKA-GGQTEINSLRASFDSLKQQMENVGSSHIQLA 95
Cdd:cd07672    2 TSTGGYDCIIQHLNDGRKNCKEFEDFLKERASIEEKYGKELLNLSKKKpCGQTEINTLKRSLDVFKQQIDNVGQSHIQLA 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  96 LTLREELRSLEEFRERQKEQRKKYEAVMDRVQKSKLSLYKKAMESKKTYEQKCRDADDAEQAFERISANGHQKQVEKSQN 175
Cdd:cd07672   82 QTLRDEAKKMEDFRERQKLARKKIELIMDAIHKQRAMQFKKTMESKKNYEQKCRDKDEAEQAVNRNANLVNVKQQEKLFA 161

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 966952916 176 KAKQCKDSAAEAERVYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNALWVHSNQLSMQCVKDDELYEEVR 253
Cdd:cd07672  162 KLAQSKQNAEDADRLYMQNISVLDKIREDWQKEHVKACEFFEKQECERINFFRNAVWTHVNQLSQQCVTSDEMYEEVR 239

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Schizosaccharomyces pombe Cdc15, and similar proteins; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. This subfamily is composed of Schizosaccharomyces pombe Cdc15 and Imp2, and similar proteins. These proteins contain an N-terminal F-BAR domain and a C-terminal SH3 domain. S. pombe Cdc15 and Imp2 play both distinct and overlapping roles in the maintenance and strengthening of the contractile ring at the division site, which is required in cell division. Cdc15 is a component of the actomyosin ring and is required in normal cytokinesis. Imp2 colocalizes with the medial ring during septation and is required for normal septation. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  21 GYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQTEINSLRASFDSLKQQMENVGSSHIQLALTLRE 100
Cdd:cd07651    6 GFDVIQTRIKDSLRTLEELRSFYKERASIEEEYAKRLEKLSRKSLGGSEEGGLKNSLDTLRLETESMAKSHLKFAKQIRQ 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916 101 ELRS-LEEFRERQKEQRKKYEAVMDRVQKSKLSLYKKAMESKKTYEQKCRDAddaeQAFERISANGHQKQVEKSQNKAKQ 179
Cdd:cd07651   86 DLEEkLAAFASSYTQKRKKIQSHMEKLLKKKQDQEKYLEKAREKYEADCSKI----NSYTLQSQLTWGKELEKNNAKLNK 161

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 966952916 180 CKDSAAEAERVYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNALWVHSNQLSMQCVKDDELYEEVRL 254
Cdd:cd07651  162 AQSSINSSRRDYQNAVKALRELNEIWNREWKAALDDFQDLEEERIQFLKSNCWTFANNISTLCVDDDESCERIRS 236

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of FCH domain Only proteins; F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Proteins in this group have been named FCH domain Only (FCHO) proteins. Vertebrates have two members, FCHO1 and FCHO2. These proteins contain an F-BAR domain and a C-terminal domain of unknown function named SAFF which is also present in endophilin interacting protein 1. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  19 HTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQTEINSLRASFDSLKQQMENVGSSHIQLALTL 98
Cdd:cd07648    4 NNGFDVLYHNMKHGQIAVKELADFLRERATIEETYSKALNKLAKQASNSSQLGTFAPLWLVLRVSTEKLSELHLQLVQKL 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  99 REELRSLEEFRERQKEQRKKY--------EAVMdRVQKSKLSLYKkameSKKTYEQKCRDADDAEQaferisANGHQKQV 170
Cdd:cd07648   84 QELIKDVQKYGEEQHKKHKKVkeeesgtaEAVQ-AIQTTTAALQK----AKEAYHARCLELERLRR------ENASPKEI 152

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916 171 EKSQNKAKQCKDSaaeaervYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNALWVHSNQLSMQCVKDDELYE 250
Cdd:cd07648  153 EKAEAKLKKAQDE-------YKALVEKYNNIRADFETKMTDSCKRFQEIEESHLRQMKEFLASYAEVLSENHSAVGQVHE 225

                        250       260       270
                 ....*....|....*....|....*....|....*
gi 966952916 251 EVRLTLEGCSIDADIDGFIQAKSTGTEPPAPVPYQ 285
Cdd:cd07648  226 EFKRQVDELTVDKLLRQFVESKGTGTEKPELIEFE 260

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 966952916   360 PAQEYRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERN-GQRGFVPGSYLE 414
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGrGKEGLFPSNYVE 56

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 966952916 364 YRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVE-RNGQRGFVPGSY 412
Cdd:cd00174    2 ARALYDYEAQDDDELSFKKGDIITVLEKDDDGWWEGElNGGREGLFPANY 51

Fes/CIP4 homology domain; Alignment extended from original report. Highly alpha-helical. Also known as the RAEYL motif or the S. pombe Cdc15 N-terminal domain.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916    12 WCRDFTAHTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARK----AGGQTEINSLRASFDSLKQQMENV 87
Cdd:smart00055   1 MGFWSELDDGFEALLSRLKNGLRLLEDLKKFMRERAKIEEEYAKKLQKLSKKlravRDTEPEYGSLSKAWEVLLSETDAL 80

                   ....*..
gi 966952916    88 GSSHIQL 94
Cdd:smart00055  81 AKQHLEL 87

Fes/CIP4, and EFC/F-BAR homology domain; Alignment extended from. Highly alpha-helical. The cytosolic endocytic adaptor proteins in fungi carry this domain at the N-terminus; several of these have been referred to as muniscin proteins. These N-terminal BAR, N-BAR, and EFC/F-BAR domains are found in proteins that regulate membrane trafficking events by inducing membrane tubulation. The domain dimerizes into a curved structure that binds to liposomes and either senses or induces the curvature of the membrane bilayer to cause biophysical changes to the shape of the bilayer; it also thereby recruits other trafficking factors, such as the GTPase dynamin. Most EFC/F-BAR domain-family members localize to actin-rich structures.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 966952916   21 GYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQ-----TEINSLRASFDSLKQQMENVGSSHIQ 93
Cdd:pfam00611   1 GFKVLLKRLKQGIKLLEELASFLKERAEIEEEYAKKLQKLAKKFLKKkkkpeDDGGTLKKAWDELLTETEQLAKQHLK 78

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 966952916 365 RALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLE 414
Cdd:cd11823    3 KALYSYTANREDELSLQPGDIIEVHEKQDDGWWLGELNGKKGIFPATYVE 52

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 966952916 364 YRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLE 414
Cdd:cd11772    2 FRALYDYEAQHPDELSFEEGDLLYISDKSDPNWWKATCGGKTGLIPSNYVE 52

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 966952916 365 RALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLEK 415
Cdd:cd11827    3 KALYAYDAQDTDELSFNEGDIIEILKEDPSGWWTGRLRGKEGLFPGNYVEK 53

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 966952916 365 RALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLE 414
Cdd:cd11826    3 VALYDYTADKDDELSFQEGDIIYVTKKNDDGWYEGVLNGVTGLFPGNYVE 52

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 966952916 364 YRALYDYTAQNPDELDLSAGDILEVILE-GEDGWWT-VERNGQRGFVPGSYLE 414
Cdd:cd11763    2 VRALYDFDSQPSGELSLRAGEVLTITRQdVGDGWLEgRNSRGEVGLFPSSYVE 54

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 966952916  364 YRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLEKL 416
Cdd:pfam07653   2 GRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGETGGRVGLVPSTAVEEI 54

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 966952916 365 RALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLE 414
Cdd:cd11874    3 KVLFSYTPQNEDELELKVGDTIEVLGEVEEGWWEGKLNGKVGVFPSNFVK 52

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 966952916 364 YRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVE--RNGQRGFVPGSY 412
Cdd:cd11845    2 YVALYDYEARTDDDLSFKKGDRLQILDDSDGDWWLARhlSTGKEGYIPSNY 52

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Nitric Oxide Synthase TRaffic INducer (NOSTRIN); F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Nitric Oxide Synthase TRaffic INducer (NOSTRIN) is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). NOSTRIN facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of NOSTRIN may be correlated to preeclampsia. NOSTRIN contains an N-terminal F-BAR domain and a C-terminal SH3 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules. The F-BAR domain of NOSTRIN is necessary and sufficient for its membrane association and is responsible for its subcellular localization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  16 FTAHTGYEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKA--GGQTEINSLRASFDSLKQQMENVGSSHIQ 93
Cdd:cd07658    1 FMGQKGFEELRRYVKQGGDFCKELATVLQERAELELNYAKGLSKLSGKLskASKSVSGTLSSAWTCVAEEMESEADIHRN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  94 LALTLREEL-RSLEEFRERQKEQRKKYEAVMDRV-----------QKSKLSLYKKAMESKKTYEQKCRDADDAEQAFERI 161
Cdd:cd07658   81 LGSALTEEAiKPLRQVLDEQHKTRKPVENEVDKAaklltdwrseqIKVKKKLHGLARENEKLQDQVEDNKQSCTKQKMLN 160

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 966952916 162 ----SANGHQKQVEKSQNKAKQCKDSAAEAERVYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNAL 231
Cdd:cd07658  161 klkkSAEVQDKEDEKLEAKRKKGEESRLKAENEYYTCCVRLERLRLEWESALRKGLNQYESLEEERLQHLKHSL 234

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 966952916 363 EYRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLEK 415
Cdd:cd11873    1 EVIVEFDYDAEEPDELTLKVGDIITNVKKMEEGWWEGTLNGKRGMFPDNFVKV 53

The F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of Protein kinase C and Casein kinase Substrate in Neurons 1 (PACSIN1); F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization. Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSIN 1 or Syndapin I is expressed specifically in the brain and is localized in neurites and synaptic boutons. It binds the brain-specific proteins dynamin I, synaptojanin, synapsin I, and neural Wiskott-Aldrich syndrome protein (nWASP), and functions as a link between the cytoskeletal machinery and synaptic vesicle endocytosis. PACSIN 1 interacts with huntingtin and may be implicated in the neuropathology of Huntington's disease. It contains an N-terminal F-BAR domain and a C-terminal SH3 domain. F-BAR domains form banana-shaped dimers with a positively-charged concave surface that binds to negatively-charged lipid membranes. They can induce membrane deformation in the form of long tubules.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  22 YEVLLQRLLDGRKMCKDMEELLRQRAQAEERYGKELVQIARKAGGQTE----INSLRASFDSLKQQMENVGSSHIQLALT 97
Cdd:cd07680    7 YKRTVKRIDDGHRLCNDLMNCVQERAKIEKAYGQQLTDWAKRWRQLIEkgpqYGSLERAWGAIMTEADKVSELHQEVKNN 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966952916  98 LREElrSLEEFRERQKE-----------QRKKYEAVMDRVQKSKLSLYKKAMESKKTYEQKCRDADDA--EQAFERISAN 164
Cdd:cd07680   87 LLNE--DLEKVKNWQKDayhkqimggfkETKEAEDGFRKAQKPWAKKMKELEAAKKAYHLACKEEKLAmtREANSKAEQS 164

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 966952916 165 GHQKQVEKSQNKAKQCKDSAAEAERVYRQSITQLEKVRAEWEQEHRTTCEAFQLQEFDRLTILRNAL 231
Cdd:cd07680  165 VTPEQQKKLQDKVDKCKQDVQKTQEKYEKVLDDVGKTTPQYMENMEQVFEQCQQFEEKRLVFLKEVL 231

Third (or C-terminal) Src Homology 3 domain of Sorbin and SH3 domain containing 1 (Sorbs1), also called ponsin; Sorbs1 is also called ponsin, SH3P12, or CAP (c-Cbl associated protein). It is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It binds Cbl and plays a major role in regulating the insulin signaling pathway by enhancing insulin-induced phosphorylation of Cbl. Sorbs1, like vinexin, localizes at cell-ECM and cell-cell adhesion sites where it binds vinculin, paxillin, and afadin. It may function in the control of cell motility. Other interaction partners of Sorbs1 include c-Abl, Sos, flotillin, Grb4, ataxin-7, filamin C, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 966952916 364 YRALYDYTAQNPDELDLSAGDILEVILEGEDGWW--TVERNGQRGFVPGSYLEKL 416
Cdd:cd11916    4 YQALYSYAPQNDDELELRDGDIVDVMEKCDDGWFvgTSRRTKQFGTFPGNYVKLL 58

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic protein that binds focal adhesion proteins and is involved in cell signaling, migration, and proliferation. It is overexpressed in several cancer cells including breast, ovarian, bladder, and liver. In cancer cells, it can be found in the nucleus; its degree of nuclear localization correlates with tumor size and poor prognosis. Lasp1 is a 36kD protein containing an N-terminal LIM domain, two nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 966952916 361 AQEYRALYDYTAQNPDELDLSAGDILEVILEGEDGWW--TVERNGQRGFVPGSYLEKL 416
Cdd:cd11934    2 GKRYRAVYDYNAADEDEVSFQDGDTIVNVQQIDDGWMygTVERTGDTGMLPANYVEAI 59

Src homology 3 domain of Alpha Spectrin; Spectrin is a major structural component of the red blood cell membrane skeleton and is important in erythropoiesis and membrane biogenesis. It is a flexible, rope-like molecule composed of two subunits, alpha and beta, which consist of many spectrin-type repeats. Alpha and beta spectrin associate to form heterodimers and tetramers; spectrin tetramer formation is critical for red cell shape and deformability. Defects in alpha spectrin have been associated with inherited hemolytic anemias including hereditary spherocytosis (HSp), hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis (HPP). Alpha spectrin contains a middle SH3 domain and a C-terminal EF-hand binding motif in addition to multiple spectrin repeats. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 966952916 366 ALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLEK 415
Cdd:cd11808    4 ALYDYQEKSPREVSMKKGDILTLLNSSNKDWWKVEVNDRQGFVPAAYVKK 53

First Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 966952916 366 ALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERN--GQRGFVPGSYLEK 415
Cdd:cd11761    6 VLYSYEAQRPDELTITEGEELEVIEDGDGDGWVKARNksGEVGYVPENYLQF 57

C-terminal Src Homology 3 domain of Nebulette and LIM-nebulette (or Lasp2); Nebulette is a cardiac-specific protein that localizes to the Z-disc. It interacts with tropomyosin and is important in stabilizing actin thin filaments in cardiac muscles. Polymorphisms in the nebulette gene are associated with dilated cardiomyopathy, with some mutations resulting in severe heart failure. Nebulette is a 107kD protein that contains an N-terminal acidic region, multiple nebulin repeats, and a C-terminal SH3 domain. LIM-nebulette, also called Lasp2 (LIM and SH3 domain protein 2), is an alternatively spliced variant of nebulette. Although it shares a gene with nebulette, Lasp2 is not transcribed from a muscle-specific promoter, giving rise to its multiple tissue expression pattern with highest amounts in the brain. It can crosslink actin filaments and it affects cell spreading. Lasp2 is a 34kD protein containing an N-terminal LIM domain, three nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 966952916 364 YRALYDYTAQNPDELDLSAGDILEVILEGEDGWW--TVERNGQRGFVPGSYLE 414
Cdd:cd11935    3 YRAMYDYSAQDEDEVSFRDGDYIVNVQPIDEGWMygTVQRTGRTGMLPANYIE 55

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 966952916 364 YRALYDYTAQNPDELDLSAGDILEVILEGEDGWWTVERNGQRGFVPGSYLE 414
Cdd:cd11877    2 VRAKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGTLNGKTGWFPSNYVK 52